The clinical significance of the proposed studies on brain fuel transport and microvascular metabolism is twofold. First, hypoglycemia is a common, sometimes devastating effect of insulin or sulfonylurea treatment. Hypoglycemia limits diabetes therapy. Striving for euglycemia to thwart long term complications may risk hypoglycemia severe enough to cause brain dysfunction and damage. Both diabetes and chronic hypoglycemia alter brain fuel transport and microvascular metabolism in a parallel manner. Diabetes decreases brain microvascular glucose transport and metabolism. Conversely, in rats with chronic hypoglycemia both increase. This proposal examines the mechanisms and consequences of these changes in transport and metabolism. Second, diabetes increases both stroke risk and damage. Abnormal brain microvascular metabolism could account for the increased stroke damage. Several hypotheses underlie the proposed work. First, chronic changes in both plasma glucose and insulin levels specifically modify brain transport and its microvascular fuel metabolism. Second, fuel metabolism probably influences glucose transport, although metabolism and transport may simply undergo coordinate regulation. Third, a unique glucose transport protein exists in brain parenchyma which may be affected by diabetes or hypoglycemia. Last, high rates of oxygen consumption and disturbed fuel metabolism in diabetic brain microvessels impair their tolerance to ischemia. To evaluate these hypotheses, studies will be performed with the following aims: 1. Determine the influence of chronic changes in the plasma glucose and insulin concentrations on brain microvascular hexose transport in vivo; 2. Characterize hexose transport by brain microvessels and parenchyma in vitro in experimental diabetes and hypoglycemia; 3. Evaluate possible molecular mechanisms whereby glucose transport is modulated; 4. Examine the interrelationship between brain microvascular fuel metabolism and hexose transport in diabetes and hypoglycemia; and 5. Determine whether the changes in fuel metabolism induced by diabetes impair the ability of the brain microvessels to maintain their energy status (ATP and ATP/ADP ratio) when fuel deprived or made anoxic in vitro. These studies will advance understanding of the regulation of brain hexose transport, its relation to microvascular fuel metabolism, and the molecular mechanisms altering it. They may also help explain why diabetes reduces cerebrovascular tolerance to ischemia.